Abstract
Electrophiles can activate redox signal transduction pathways, through actions of effector molecules (e.g., kinases and transcription factors) and sensor proteins with low pKa thiols that are covalently modified. In this study, we investigated whether 1,4-naphthoquinone (1,4-NQ) could affect the phosphatase and tensin homolog (PTEN)–Akt signaling pathway and persulfides/polysulfides could modulate this adaptive response. Simultaneous exposure of primary mouse hepatocytes to Na2S4 and 1,4-NQ markedly decreased 1,4-NQ-mediated cell death and S-arylation of cellular proteins. Modification of cellular PTEN during exposure to 1,4-NQ was also blocked in the presence of Na2S4. 1,4-NQ, at up to 10 µM, increased phosphorylation of Akt and cAMP response element binding protein (CREB). However, at higher concentrations, 1,4-NQ inhibited phosphorylation of both proteins. These bell-shaped dose curves for Akt and CREB activation were right-shifted in cells treated with both 1,4-NQ and Na2S4. Incubation of 1,4-NQ with Na2S4 resulted in formation of 1,4-NQ–S–1,4-NQ-OH. Unlike 1,4-NQ, authentic 1,4-NQ-S-1,4-NQ-OH adduct had no cytotoxicity, covalent binding capability nor ability to activate PTEN-Akt signaling in cells. Our results suggested that polysulfides, such as Na2S4, can increase the threshold of 1,4-NQ for activating PTEN–Akt signaling and cytotoxicity by capturing this electrophile to form its sulfur adducts.
Highlights
There are a variety of cellular redox signaling processes, involving sensor proteins with low pKa thiol groups and effector molecules
Collaborating with Nishida et al, we reported that endogenous and exogenous electrophiles activated the H-Ras signaling pathway, through S-modification of H-Ras, and that this electrophilic signaling was negatively regulated by hydrogen sulfide (H2S) produced by cystathionine γ-lyase (CSE), and cystathionine β-synthase (CBS)[17]
We recently found that overexpression and knockdown of CBS and CSE enhanced and decreased, respectively, activation of the heat shock protein 90 (HSP90)–heat shock factor 1 (HSF1) signaling pathway by environmental electrophiles such as cadmium (Cd) and 1,4-NQ18, 19
Summary
There are a variety of cellular redox signaling processes, involving sensor proteins with low pKa thiol groups and effector molecules (e.g., kinases and transcription factors). Collaborating with Nishida et al, we reported that endogenous and exogenous electrophiles activated the H-Ras signaling pathway, through S-modification of H-Ras, and that this electrophilic signaling was negatively regulated by hydrogen sulfide (H2S) produced by cystathionine γ-lyase (CSE), and cystathionine β-synthase (CBS)[17] These observations suggested that H-Ras signaling, and other redox signaling pathways that can be activated by electrophiles, are potentially modulated by sulfur species. In a cell-free study, the enzymatic reaction of CSE in the presence of 1,4-NQ produced 1,4-NQ–sulfur adducts such as 1,4-NQ–S–1,4-NQ [(1,4-NQ)2S], produced by reaction of 1,4-NQ with H2S19 From these observations we hypothesized that reactive per/polysulfides, could suppress 1,4-NQ-mediated modulation of HSP90–HSF1 signaling, by capturing 1,4-NQ involved in its sulfur adduct formation. We investigated activation of the PTEN–Akt signaling pathway by 1,4-NQ and the contributions of persulfides/polysulfides to modulation of this signaling
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call